A polygenic risk score for Alzheimer's disease (AD) is tied to several markers of AD in older participants and to smaller hippocampal volume in younger participants. The results of the small study, published in Neurology, may provide some evidence of the effects of aggregate genetic risk before AD is clinically apparent.

“The stage of Alzheimer's before symptoms show up is thought to last over a decade. Given that current clinical trials are testing whether therapies can slow memory and thinking decline among people at risk for the disease, it is critical to understand the influence of risk factors before symptoms are present,” study author Elizabeth C. Mormino, PhD, of Massachusetts General Hospital in Charlestown, MA, said in a press release.

Dr Mormino and colleagues calculated polygenic risk scores (PGRS) using data from the International Genomics of Alzheimer's Project to investigate the associations between PGRS and markers of AD including β-amyloid, hippocampal volume, clinical progression, and cognitive decline.

The study included 166 participants with AD and 1031 participants who were clinically normal or had mild cognitive impairment (MCI). Data was also analyzed to investigate possible associations between PGRS and hippocampal volume in clinically normal participants aged 18 to 35 years (n=1322).

The investigators found that an elevated PGRS in patients without dementia was associated with both decreased memory performance (P=.002) and smaller hippocampal volume (P=.002) at baseline. Likewise, there was significant interaction between PGRS and greater longitudinal cognitive decline (executive function: P=.01; memory: P=.0005) and clinical progression (P<.00001).

During the 3 year follow-up, 15 clinically normal participants and 143 participants with MCI developed clinical progression. Logistic regression analysis indicated an increased risk for progression with elevated PGRS (P<.00001). Further analysis indicated that baseline hippocampal volume and PGRS were independently associated with risk for clinical progression (PGRS P=.00004, HV P<.0001), executive function change (PGRS P=.07, HV P<.0001), and memory change (PGRS P=.0041, HV P<.0001). Smaller hippocampal volume in the younger, clinically normal group was also associated with elevated PGRS (P=.05). The authors noted that this relationship was evident when examining PGRS that included many loci below the genome-wise association study (GWAS)-level significance threshold (16 123 single nucleotide polymorphisms), however it was not evident when restricted to GWAS-level significant loci (18 single nucleotide polymorphisms).

Additionally, a higher PGRS was tied to β-amyloid burden — similar to what is seen in AD — on florbetapir PET scan (P=.03); however the relationship was not statistically significant for CSF β-amyloid (P=.11). .

“Our study was small and larger numbers of participants will need to be studied to confirm our findings,” Dr Mormino said. “The goal of this type of research is to help physicians better identify those at high risk of dementia so that future preventative treatments may be used as early as possible.”

The results highlight the importance of evaluating and monitoring cognitive function in individuals with recent critical illness or major infections, especially if they are already at risk for dementia.